Long-Term Post-COVID-19 Associated Oral Inflammatory Sequelae

Abstract

The oral cavity remains an underappreciated site for SARS-CoV-2 infection despite the myriad oral conditions observed in COVID-19 patients. Recently, replicating SARS-CoV-2 was found inside salivary epithelial cells resulting in inflammation and atrophy of salivary glands. Saliva possesses healing properties crucial for maintaining the health of the oral mucosa. Specifically, salivary antimicrobial peptides, most notable, histatin-5 exclusively produced in salivary glands, plays a vital role in innate immunity against colonizing microbial species. The demonstration of SARS-CoV-2 destruction of gland tissue where histatin-5 is produced strongly indicate that histatin-5 production is compromised due to COVID-19. Here we present a case of a patient presenting with unexplained chronic oral dysesthesia and dysgeusia post-recovery from COVID-19. To explore potential physiological mechanisms behind the symptoms, we comparatively analyzed saliva samples from the patient and matched healthy subject for histatin-5 and key cytokines. Findings demonstrated significantly reduced histatin-5 levels in patient's saliva and activation of the Th17 inflammatory pathway. As histatin-5 exhibits potent activity against the opportunistic oral pathogen Candida albicans, we evaluated saliva potency against C. albicans ex vivo. Compared to control, patient saliva exhibited significantly reduced anti-candidal efficacy. Although speculative, based on history and salivary analysis we hypothesize that salivary histatin-5 production may be compromised due to SARS-CoV-2 mediated salivary gland destruction. With the current lack of emphasis on implications of COVID-19 on oral health, this report may provide lacking mechanistic insights that may lead to reassessment of risks for oral opportunistic infections and mucosal inflammatory processes in acutely-ill and recovered COVID-19 patients.

Keywords: COVID - 19; antimicrobial peptide; inflammation; opportunistic infection; oral; salivary glands.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Alfaifi, Sultan, Montelongo-Jauregui, Meiller and Jabra-Rizk.

Figures

Figure 1

Ex vivo evaluation of anti-candidal activity of patient and control subject saliva based on reduction in C. albicans CFU counts. When the patient (P) and control subject (C) saliva samples with pre-determined Hst-5 levels were used in our Candida killing assay, both patient samples exhibited significantly reduced inhibitory effect on C. albicans compared to the control samples. The percent killing of the patient samples was proportional to measured Hst-5 concentration (P-S1: 1µg/l; P-S2: 2.3µg/ml). Purified Hst-5 peptide (5-20 µg/ml) was used as positive control for killing, and PBS as negative control. *P = 0.03; **P < 0.0021; ***P < 0.0002.

Figure 2

A hypothetical mechanistic illustration of the impact of COVID-19 on salivary glands and histatin production and secretion into saliva potentially predisposing patients to opportunistic infections and mucosal tissue inflammation. A schematic of a salivary gland depicting: Enrichment of viral entry factors (receptors) and replication of SARS-CoV-2 in gland serous acini and ducts; Resulting lymphocytic sialadenitis, architectural distortion, ductal rupture and atrophy of infected SG; Localization of histatin in the serous acinar and duct cells; Release of histatin and inflammatory cytokines into saliva.